Tumor-associated mutations inO6-methylguanine DNA-methyltransferase (MGMT) reduce DNA repair functionality

MGMT is the primary vehicle for cellular removal of alkyl lesions from the O-6 position of guanine and the O-4 position of thymine. While key to the maintenance of genomic integrity, MGMT also removes damage induced by alkylating chemotherapies, inhibiting the efficacy of cancer treatment. Germline variants of human MGMT are well-characterized, but somatic variants found in tumors were, prior to this work, uncharacterized. We found that MGMT G132R, from a human esophageal tumor, and MGMT G156C, from a human colorectal cancer cell line, are unable to rescue methyltransferase-deficient Escherichia coli as well as wild type (WT) human MGMT after treatment with a methylating agent. Using pre-steady state kinetics, we biochemically characterized these variants as having a reduced rate constant. G132R binds DNA containing an O6-methylguanine lesion half as tightly as WT MGMT, while G156C has a 40-fold decrease in binding affinity for the same damaged DNA versus WT. Mammalian cells expressing either G132R or G156C are more sensitive to methylating agents than mammalian cells expressing WT MGMT. G132R is slightly resistant to O6-benzylguanine, an inhibitor of MGMT in clinical trials, while G156C is almost completely resistant to this inhibitor. The impared functionality of expressed variants G132R and G156C suggests that the presence of somatic variants of MGMT in a tumor could impact chemotherapeutic outcomes.

Supersonic flutter of composite skin panels of repeated-sublaminate layup

In high-speed aerospace vehicles, supersonic flutter is a well-known phenomenon of dynamic instability to which external skin panels are prone. In theory, the instability stage is expressed by the 'flutter critical parameter' Q(crit), which is a function of the stiffness-, and dynamic pressure parameters. For a composite skin panel, Q(crit) can be maximised by lay-up optimisation. Repeated-sublaminate lay-up schemes possess good potential for economical lay-up optimisation because the corresponding effort is limited to a family of sublaminates of few layers only. When Q(crit) is obtained for all sublaminates of a family, and the sublaminates ranked accordingly, the resulting ranking reveals not only the optimum lay-up, but also the near-optimum lay-ups, which are useful design alternatives, and the inferior lay-ups which should be avoided. In this paper, we examine sublaminate-ranking characteristics for a composite panel prone to supersonic flutter. In particular, we consider a simple supported midplane-symmetrical rectangular panel of typical aspect ratio alpha and flow angle psi, and for four-layered sublaminates, obtain the Q(crit)-based rankings for a wide range of the number of repeats, r. From the rankings, we find that an optimum lay-up can exist for which the outermost layer is oriented wide of, rather than along, the flow. Furthermore, for many lay-ups other than the optimum and the inferior, we see that as r increases, Q(crit) undergoes significant change in the course of converging. To reconcile these findings, eigenvalue-coalescence characteristics are discussed in detail for specific cases.

Gel-coated ion-exchange resin: A new kinetic model

Regenerable 'gel-coated' cationic resins with fast sorption kinetics and high sorption capacity have application potential for removal of trace metal ions even in large-scale operations. Poly(acrylic acid) has been gel-coated on high-surface area silica (pre-coated with ethylene-vinyl acetate copolymer providing a thin barrier layer) and insolubilized by crosslinking with a low-molecular-weight diepoxide (epoxy equivalent 180 g) in the presence of benzyl dimethylamine catalyst at 70 degrees C, In experiments performed for Ca2+ sorption from dilute aqueous solutions of Ca(NO,),, the gel-coated acrylic resin is found to have nearly 40% higher sorption capacity than the bead-form commercial methacrylic resin Amberlite IRC-50 and also several limes higher rate of sorption. The sorption on the gel-coated sorbent under vigorous agitation has the characteristics of particle diffusion control with homogeneous (gel) diffusion in resin phase. A new mathematical model is proposed for such sorption on gel-coated ion-exchange resin in finite bath and solved by applying operator-theoretic methods. The analytical solution so obtained shows goad agreement with experimental sorption kinetics at relatively low levels (< 70%) of resin conversion.

Development of a cultured tissue substitute to repair the ageing retina

This project provides a foundation for the use of silk membranes in a tissue engineered therapy for the treatment of devastating retinal diseases such as age-related macular degeneration. The three-dimensional tissue model described in this thesis has great potential for use in basic research of retinal pathologies, and the potential to be implemented into clinical approaches after appropriate refinement.

Analysis Of Curved Laminated Beams Of Bimodulus Composite-Materials

Composite materials exhibiting different moduli in tension and in compression, commonly called as bimodular composites are being used in many engineering fields. A finite element analysis is carried out for small deflection static behavior of laminated curved beams of bi modulus materials for both solid and hollow circular cross-sections using an iterative procedure. The finite element has 16 d.o.f. and uses the displacement field in terms of first order Hermite in terpolation polynomials. The neutral surface, i.e. the locus of points having zero axial strain is found to vary drastically depending on the loading, lay up schemes and radius of curvature. As il lustrations, plots of the cross-sections of the ruled neutral-surface are presented for some of the investigated cases. Using this element a few problems of curved laminated beams of bimodulus materials are solved for both solid and hollow circular cross-sections.

Fasteners in Composite Plates - Effects of Interfacial Friction

The effects of tangential friction at pin—hole interfaces are appropriately modelled for the analysis of fasteners in large composite (orthotropic) plate loaded along its edges. The pin—hole contact could be of interference, clearance or neat fit. When the plate load is monotonically increased, interference fits give rise to receding contact, whereas clearance fits result in advancing contact. In either case, the changing contact situations lead to non-linear moving boundary value problems. The neat fit comes out as a special case in which the contact and separation regions are invariant with the applied load level and so the problem remains linear. The description of boundary conditions in the presence of tangential friction, will depend on whether the problem is one of advancing or receding contact, advancing contact presenting a special problem. A model is developed for the limiting case of a rigid pin and an ideally rough interface (infinitely large friction coefficient). The non-linearity resulting from the continuously varying proportions of contact and separation at the interface, is handled by an “Inverse Formulation” which was successfully applied earlier by the authors for smooth (zero friction) interfacial conditions. The additional difficulty introduced by advancing contact is handled by adopting a “Marching Solution”. The modelling and the procedure are illustrated in respect of symmetric plate load cases. Numerical results are presented bringing out the effects of interfacial friction and plate orthotropy on load-contact relations and plate stresses.

Action of Transition Metal Oxides on Composite Solid Propellants

The catalytic effects of Fe2O3, Ni2O3, MnO2, and Co2O3 transition metal oxides (TMO) on the combustion of polystyrene and carboxyl-terminated polybutadiene were investigated. The order of activity of TMO's was explained by the presence of Co and absence of Fe and Ni in their lattice systems along with a reduced electron-transfer process; in systems which induce the metal ions to enter the lattice, the electron transfer process is much greater. The thermal decomposition of ammonium perchlorate propellants was enhanced to a greater extent by Co2O3 and MnO2 than by Fe2O3 and Ni2O3.

Instability of laminated composite thin-walled open-section beams

Instability of thin-walled open-section laminated composite beams is studied using the finite element method. A two-noded, 8 df per node thin-walled open-section laminated composite beam finite element has been used. The displacements of the element reference axis are expressed in terms of one-dimensional first order Hermite interpolation polynomials, and line member assumptions are invoked in formulation of the elastic stiffness matrix and geometric stiffness matrix. The nonlinear expressions for the strains occurring in thin-walled open-section beams, when subjected to axial, flexural and torsional loads, are incorporated in a general instability analysis. Several problems for which continuum solutions (exact/approximate) are possible have been solved in order to evaluate the performance of finite element. Next its applicability is demonstrated by predicting the buckling loads for the following problems of laminated composites: (i) two layer (45°/−45°) composite Z section cantilever beam and (ii) three layer (0°/45°/0°) composite Z section cantilever beam.

Analysis of a finite composite plate with smooth rigid pin

A continuum method of analysis is presented in this paper for the problem of a smooth rigid pin in a finite composite plate subjected to uniaxial loading. The pin could be of interference, push or clearance fit. The plate is idealized to an orthotropic sheet. As the load on the plate is progressively increased, the contact along the pin-hole interface is partial above certain load levels in all three types of fit. In misfit pins (interference or clearance), such situations result in mixed boundary value problems with moving boundaries and in all of them the arc of contact and the stress and displacement fields vary nonlinearly with the applied load. In infinite domains similar problems were analysed earlier by ‘inverse formulation’ and, now, the same approach is selected for finite plates. Finite outer domains introduce analytical complexities in the satisfaction of boundary conditions. These problems are circumvented by adopting a method in which the successive integrals of boundary error functions are equated to zero. Numerical results are presented which bring out the effects of the rectangular geometry and the orthotropic property of the plate. The present solutions are the first step towards the development of special finite elements for fastener joints.

Exploring methods of preparing functional cartilage-bone xenografts for joint repair

This thesis explores the feasibility of donor-receiver concept for joint replacement where cartilage-bone tissues can be taken from either human or other mammals and prepared scientifically for repairing focal joint defects in knees, hips and shoulders. The manufactured construct is immunologically inert and is capable of acting as a scaffold for engineering new cartilage-bone laminates when placed in the joint. Innovative manufacturing procedures and assessment techniques were developed for appraising this tissue-based scaffold. This research has demonstrated that tissue replacement technology can be applied in situations where blood vessels are absent such as in articular cartilage.

Composite field approximations for ion traps with apertures on electrodes

This paper presents two approximate analytical expressions for nonlinear electric fields in the principal direction in axially symmetric (3D) and two dimensional (2D) ion trap mass analysers with apertures (holes in case of 3D traps and slits in case of 2D traps) on the electrodes. Considered together (3D and 2D), we present composite approximations for the principal unidirectional nonlinear electric fields in these ion traps. The composite electric field E has the form E = E-noaperture + E-aperture. where E-noaperture is the field within an imagined trap which is identical to the practical trap except that the apertures are missing and E-aperture is the field contribution due to apertures on the two trap electrodes. The field along the principal axis, of the trap can in this way be well approximated for any aperture that is not too large. To derive E-aperture. classical results of electrostatics have been extended to electrodes with finite thickness and different aperture shapes.E-noaperture is a modified truncated multipole expansion for the imagined trap with no aperture. The first several terms in the multipole expansion are in principle exact(though numerically determined using the BEM), while the last term is chosen to match the field at the electrode. This expansion, once Computed, works with any aperture in the practical trap. The composite field approximation for axially symmetric (3D) traps is checked for three geometries: the Paul trap, the cylindrical ion trap (CIT) and an arbitrary other trap. The approximation for 2D traps is verified using two geometries: the linear ion trap (LIT) and the rectilinear ion trap (RIT). In each case, for two aperture sizes (10% and 50% of the trap dimension), highly satisfactory fits are obtained. These composite approximations may be used in more detailed nonlinear ion dynamics Studies than have been hitherto attempted. (C) 2009 Elsevier B.V. All rights reserved.

Co-assembly of a Nafion-Mesoporous Zirconium Phosphate Composite Membrane for PEM Fuel Cells

Synthesis of mesoporous zirconium phosphate (MZP) by co-assembly of a tri-block copolymer, namely pluronic-F127, as a structure-directing agent, and a mixture of zirconium butoxide and phosphorous trichloride as inorganic precursors is reported. MZP with a specific surface area of 84 m(2) g(-1) average pore diameter of about 17 nm and pore volume of 0.35 cm(3) g(-1) has been prepared, and characterised by X-ray diffraction (XRD) and transmission electron microscopy. Nafion-MZP composite membrane is obtained by employing MZP as a surface-functionalised solid-super-acid-proton-conducting medium as well as all inorganic filler with high affinity to absorb water and fast proton-transport across the electrolyte membrane even under low relative humidity (RH) conditions. The composite membranes have been evaluated in H-2/O-2 polymer electrolyte fuel cells (PEFCs) at varying RH values between 18 and 100%; a peak power density of 355 mW cm(-2) at a load current density of 1,100 mA cm(-2) is achieved with the PEFC employing Nafion-MZP composite membrane while operating at optimum temperature (70 degrees C) under 18% RH and ambient pressure. On operating the PEFC employing Nafion-MZP membrane electrolyte with hydrogen and air feeds at ambient pressure and a RH value of 18%, a peak power density of 285 mW cm(-2) at the optimum temperature (60 degrees C) is achieved. In contrast, operating under identical conditions, a peak power density of only similar to 170 mW cm(-2) is achieved with the PEFC employing Nafion-1135 membrane electrolyte.

“We live in in a house of blo- in a block of flats.” – Self-repair in EFL Spoken Language

Tämä tutkielma on osa Helsingin yliopiston rahoittamaa HY-talk -tutkimusprojektia, jonka tavoite on vankentaa puheviestinnän, erityisesti vieraiden kielten suullisen taidon opetusta ja arviointia yleissivistävässä koulutuksessa ja korkeakouluasteella. Tämän tutkielman tavoite on selvittää millaisia korjauksia englantia vieraana kielenä puhuvat ihmiset tekevät puheeseensa ja tutkia itsekorjauksen ja sujuvuuden välistä suhdetta. Korjausjäsennystä ja itsekorjausta on aiemmin tutkittu sekä keskustelunanalyysin että psykolingvistiikan aloilla, ja vaikka tämä tutkielma onkin lähempänä aiempaa keskustelunanalyyttistä kuin psykolingvististä tutkimusta, siinä hyödynnetään molempia suuntauksia. Itsekorjausta on yleisesti pidetty merkkinä erityisesti ei-natiivien kielenpuhujien sujuvuuden puutteesta. Tämän tutkielman tarkoitus on selvittää, kuinka läheisesti itsekorjaus todella liittyy sujuvuuteen tai sen puutteeseen. Tutkielman materiaali koostuu HY-talk -projektia varten kerätyistä puhenäytteistä ja niiden pohjalta tehdyistä taitotasoarvioinneista. Puhenäytteet kerättiin vuonna 2007 projektia varten järjestettyjen puhekielen testaustilanteiden yhteydessä kolmessa eteläsuomalaisessa koulussa. Koska projektin tavoitteena on tutkia ja parantaa kielten suullisen taidon arviointia, projektissa mukana olleet kieliammattilaiset arvioivat puhujien taitotasot projektia varten (Eurooppalaisen Viitekehyksen taitotasokuvainten pohjalta) koottujen arviointiasteikoiden perusteella, ja nämä arvioinnit tallennettiin osaksi projektin materiaalia. Tutkielmassa analysoidaan itsekorjauksia aiemman psykolingvistisen tutkimuksen pohjalta kootun korjaustyyppiluokituksen sekä tätä tutkielmaa varten luodun korjausten oikeellisuutta vertailevan luokituksen avulla. Lisäksi siinä vertaillaan kahden korkeamman ja kahden matalamman taitotasoarvioinnin saaneen puhujan itsekorjauksia. Tulokset osoittavat, että ei-natiivien puheessa esiintyy monenlaisia eri korjaustyyppejä, ja että yleisimpiä korjauksia ovat alkuperäisen lausuman toistot. Yleisiä ovat myös korjaukset, joissa puhuja korjaa virheen tai keskeyttää puheensa ja aloittaa kokonaan uuden lausuman. Lisäksi tuloksista käy ilmi, ettei suurin osa korjauksista todennäköisesti johdu puhujien sujuvuuden puutteesta. Yleisimmät korjaustyypit voivat johtua suurimmaksi osaksi yksilön puhetyylistä, siitä, että puhuja hakee jotain tiettyä sanaa tai ilmausta mielessään tai siitä, että puhuja korjaa puheessaan huomaamansa kieliopillisen, sanastollisen tai äänteellisen virheen. Vertailu korkeammalle ja matalammalle taitotasolle arvioitujen puhujien välillä osoittaa selkeimmin, ettei suurin osa itsekorjauksista ole yhteydessä puhujan sujuvuuteen. Vertailusta käy ilmi, ettei pelkkä itsekorjausten määrä kerro kuinka sujuvasti puhuja käyttää kieltä, sillä toinen korkeammalle taitotasolle arvioiduista puhujista korjaa puhettaan lähes yhtä monesti kuin matalammalle tasolle arvioidut puhujat. Lisäksi korjausten oikeellisuutta vertailevan luokituksen tulokset viittaavat siihen, etteivät niin korkeammalle kuin matalammallekaan tasolle arvioidut puhujat useimmiten korjaa puhettaan siksi, etteivät pystyisi ilmaisemaan viestiään oikein ja ymmärrettävästi.

Nonlinear analysis for the pre- and post-yield behaviour of a composite structure with the refined plastic hinge approach

The computational technique of the full ranges of the second-order inelastic behaviour evaluation of steel-concrete composite structure is not always sought forgivingly, and therefore it hinders the development and application of the performance-based design approach for the composite structure. To this end, this paper addresses of the advanced computational technique of the higher-order element with the refined plastic hinges to capture the all-ranges behaviour of an entire steel-concrete composite structure. Moreover, this paper presents the efficient and economical cross-section analysis to evaluate the element section capacity of the non-uniform and arbitrary composite section subjected to the axial and bending interaction. Based on the same single algorithm, it can accurately and effectively evaluate nearly continuous interaction capacity curve from decompression to pure bending technically, which is the important capacity range but highly nonlinear. Hence, this cross-section analysis provides the simple but unique algorithm for the design approach. In summary, the present nonlinear computational technique can simulate both material and geometric nonlinearities of the composite structure in the accurate, efficient and reliable fashion, including partial shear connection and gradual yielding at pre-yield stage, plasticity and strain-hardening effect due to axial and bending interaction at post-yield stage, loading redistribution, second-order P-δ and P-Δ effect, and also the stiffness and strength deterioration. And because of its reliable and accurate behavioural evaluation, the present technique can be extended for the design of the high-strength composite structure and potentially for the fibre-reinforced concrete structure.

Flexure of composite plates

A new higher order shear deformation theory of laminated composite plates is developed. The basic displacement variables in this theory are two partial normal displacements and two in-plane displacement parameters. The governing equations are presented in the form of four simultaneous partial differential equations. The shear deformation theories of Bhimareddy and Stevens, and of Reddy are special cases of this formulation. In their models, transverse shear strains will become zero at points in the plate where displacements are constrained to be zero such as those on fixed edges. This limitation has been overcome in the present formulation.